The present invention relates to oxazole derivatives, compositions and medicaments containing the same, as well as processes for the preparation and use of such compounds, compositions, and medicaments. Such oxazole derivatives are useful in the treatment of diseases associated with inappropriate protein kinase activity.
An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 400 different known protein kinases. While three to four percent of the human genome is a code for the formation of protein kinases, there may be thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg2+ complex to said amino acid side chain. It is well established that protein kinase enzymes control a number of signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxy groups of serine, theonine, and tyrosine residues in proteins. To this end protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Furthermore, several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. The aforementioned cell processes are highly regulated, often by complex intermeshed pathways where each kinase is itself regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Consequently, due to their physiological relevance, variety, and pervasiveness, protein kinases have become one of the most important and widely studied enzyme families in biochemical and medical research.
The protein kinase family of enzymes is typically classified into two main subfamilies: protein tyrosine kinases (PTK(s)) and protein serine/theonine kinases (PSTK(s)), based on the amino acid residue phosphorylated. PSTK(s) catalyze phosphorylation of hydroxy substituents on serine or theonine side chains. PSTK(s) include cyclic AMP and cyclic GMP dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant PSTK activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, PSTK(s) and the signal transduction pathways which they are part of are important targets for drug design. PTK(s) phosphorylate hydroxy substituents on tyrosine side chains. PTK(s) are present in much smaller quantities but also play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), insulin receptor, platelet derived growth factor receptor (PDGFR), and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Aberrant PTK activity has also been implicated or suspected in a number of pathologies such as osteoarthritis, rheumatoid arthritis, psoriasis, a variety of cancers, and other proliferative diseases. Accordingly, PTK and their signal transduction pathways are also important targets for drug design.
The present invention relates to a series of substituted oxazole compounds, which exhibit PTK and/or PSTK inhibition.
In particular, these compounds exhibit inhibition of the PTK:VEGFR2. VEGFR2 kinase is found in endothelial cells and is involved in angiogenesis—the growth and proliferation of blood vessels from existing capillaries. Angiogenesis plays an important role in development, homeostasis, wound healing, the female reproductive cycle, and in pathological conditions such as rheumatoid arthritis, diabetic retinopathy, mascular degeneration, psoriasis, and cancer. The role of angiogenesis in disease states is discussed, for instance, in Fan et al, Trends in Pharmacol Sci. 16:54–66; Shawver et al, DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine 1:27–31. Activation of VEGFR2 by Vascular Endothelial Growth Factor (VEGF) is a critical step in the signal transduction pathway that initiates tumor angiogenesis. The VEGF ligand activates VEGFR2 by binding to its extracellular VEGF binding site. This leads to receptor dimerization of VEGFRs and autophosphorylation of tyrosine residues at the intracellular kinase domain of VEGFR2. The kinase domain operates to transfer a phosphate from ATP to the tyrosine residues, thus providing binding sites for signaling proteins downstream of VEGFR2 leading ultimately to angiogenesis. (Ferrara and Davis-Smyth, Endocrine Reviews, 18(1):4–25, 1997; McMahon, G., The Oncologist, Vol. 5, No. 90001, 3–10, April 2000). Solid tumors will not grow beyond 1–2 mm in size without the support of additional vascularization. Most tumor types, if not all, secrete VEGF in order to stimulate angiogenesis. Inhibition of VEGFR2 would therefore interrupt a critical process involved in tumor growth and metastasis, as well as other pathological angiogenic conditions.
In addition, these compounds exhibit inhibition of a family of PSTK(s) called cyclin dependent kinases (CDKs). Progression through the eukaryotic cell cycle is controlled by CDKs and their interaction with a family of proteins termed cyclins (Myerson, et al., EMBO Journal 1992, 11, 2909–17). The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195–7; Sherr, Cell 1993, 73, 1059–1065.). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase. Progression through S-phase requires the activity of cyclin A/CDK2 whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase. It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (Pines, Current Opinion in Cell Biology 1992, 4, 144–8; Lees, Current Opinion in Cell Biology 1995, 7, 773–80; Hunter and Pines, Cell 1994, 79, 573–82). Consequently, inhibition of CDKs may prevent progression in the cell cycle in normal cells and limit the toxicity of cytotoxics that act in S-phase, G2, or mitosis. Such disruption of the cell cycle of normal proliferating cells should therefore protect such proliferating cells such as hair follicles and epithelial mucosa from the effects of cytotoxic agents and thereby provide a potent treatment for side effects associated with cancer chemo- and radiotherapies.
The present inventors have discovered novel oxazole derivatives, which inhibit the activity of VEGFR2 and/or the CDKs, specifically CDK2 and CDK4 activity. Such oxazole derivatives are useful in the treatment of disorders associated with inappropriate VEGFR2 and/or CDK activity.